Retroviruses are viruses that contain single-stranded RNA particles enveloped in a protein capsid. The family retrovirus family consists of three groups: the spumaviruses such as the human foamy virus; the lentiviruses, such as the human immunodeficiency virus types 1 and 2, as well as visna virus of sheep; and the oncoviruses.
The retrovirus particle is composed of two identical RNA molecules. Each genome is a positive sense, single-stranded RNA molecule, which is capped at the 5′ end and polyadenylated at the 3′ tail. The prototype C-type oncoviral RNA genome contains three open reading frames call gag, pol and env, bounded by regions that contain signals essential for expression of the viral genes. The gag region encodes the structural proteins of the viral capsid. The pol region encodes a viral proteinase as well as the proteins for genome processing, including reverse transcriptase, ribonuclease H and endonuclease enzymatic activities. The env region specifies the glycoproteins of the viral envelope. In addition to these three open reading frames, the more complex genomes of the lentiviruses and the spumaviruses carry additional open reading frames, which encode regulatory proteins involved in the control of genome expression.
AIDS is a retroviral disease caused by HIV, a non-transforming human retrovirus belonging to the lentivirus family. Two genetically different but related forms of HIV, called HIV-1 and HIV-2, have been isolated from patients with AIDS. HIV-1 is the most common type associated with AIDS in the United States, Europe, and Central Africa, whereas HIV-2 causes a similar disease principally in West Africa.
Like most retroviruses, the HIV-1 virion is spherical and contains an electron-dense, cone shaped core surrounded by a lipid envelope derived from the host cell membrane. The virus core contains (1) the major capsid protein p24 (CA), (2) nucleocapsid protein p7/ p9, (3) two copies of genomic RNA, and (4) the three viral enzymes (protease (PR), reverse transcriptase (RT), and integrase). A matrix protein called p17, which lies underneath the virion envelope, surrounds the viral core. Studding the viral envelope are two viral glycoproteins, gp 120 and gp 41, which are critical for HIV infection of cells.
As with other retroviruses, the HIV proviral genome contains the gag, pol, and env genes, which code for various viral proteins. The products of the gag and pol genes are translated initially into large precursor proteins that must be cleaved by the viral protease to yield the mature proteins.
The CA is initially synthesized as a domain within a 55 kDa Gag precursor polyprotein. Approximately 4,000 copies of Gag assemble at the plasma membrane and bud to form an immature virus particle. Subsequent to budding, the CA is liberated by proteolytic cleavage of Gag, which triggers a conformational change that promotes assembly of the capsid particle. Two copies of the viral genome and enzymes essential for infectivity become encapsidated in the central, cone shaped capsid of the mature virion. The CA domain of Gag is also responsible for packaging about 200 copies of the host protein, CypA, which is a prolyl isomerase and a chaperone protein that is essential for HIV-1 infectivity. Although the precise function of CypA is not known, it is suspected that the protein facilitates disassembly of the capsid core during infectivity.
Several recent studies have shown that proper capsid assembly is critical for viral infectivity. Mutations in CA that inhibit assembly are lethal and mutations that alter capsid stability and severely attenuate replication making the CA an attractive potential antiviral target. Although antiviral agents have been developed that bind to the capsid protein of picornaviruses and suppress infectivity by inhibiting disassembly of the capsid shell, inhibitors of HIV capsid assembly or disassembly have not yet been developed as drugs.
Currently available drugs for the treatment of HIV infection target the reverse transciptase (RT) and HIV-1 protease (PR) enzymes, two of fifteen proteins encoded by the viral genome. These drugs are marginally effective when administered independently due to the rapid emergence of resistant strains that are selected under conditions of incomplete viral suppression. Sustained reductions in viral load can be achieved when RT and PR inhibitors are used in appropriate combinations (highly affective anti-retroviral therapy, HAART). But inadequate suppression due to poor compliance, resistance, and interactions with other drugs or diet is a significant problem that limits the effectiveness of HAART therapy for many patients and can lead to the spread of drug-resistant strains.
AIDS is characterized by profound immunosuppression that leads to opportunistic infections, secondary neoplasms and neurologic manifestations. In spite of the availability of HAART therapy, the mortality and morbidities associated with AIDS remain significant and unresolved by current therapies. New therapeutic compounds and methods are needed that could reduce or ameliorate the adverse events and improve the clinical outcome of AIDS, including, for example, reducing mortality and improving the quality of life of those suffering from the disease.